This application claims priority benefit under 35 U.S.C. xc2xa7 119 of European patent application No. EP 00201032.0, filed Mar. 23, 2000, and Dutch patent application No. NL 1014728, filed Mar. 23, 2000, both of which are incorporated herein by reference.
The present invention relates, among many things, to a group of novel 4,5-dihydro-1H-pyrazole compounds, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
The above mentioned 4,5-dihydro-1H-pyrazoles can be potent Cannabis-1 (CB1) receptor antagonists with utility for the treatment of psychiatric and neurological disorders.
Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J. J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB1 and CB2) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L. A.; Bonner, T. I. Cannabinoid Receptors, Pertwee, R. G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CB1 receptors in the brain, in combination with the strictly peripheral localization of the CB2 receptor, makes the CB1 receptor a very interesting molecular target for CNS-directed drug discovery in the areas of both psychiatric and neurological disorders (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1, 587. Greenberg, D. A. Drug News Perspect. 1999, 12, 458). Hitherto, three types of distinct CB1 receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB1 receptor antagonists. A representative example is SR-141716A, which is currently undergoing Phase II clinical development for psychotic disorders (Dutta, A. K.; Sard, H.; Ryan, W.; Razdan, R. K.; Compton, D. R.; Martin, B. R. Med. Chem. Res. 1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E. M.; Moerschbaecher, J. M.; Barker, L. A. CNS Drug Rev. 1999, 5, 43). Aminoalkylindoles have been disclosed as CB1 receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a CB1 receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R. M.; Hosohata, Y.; Burkey, T. H.; Makriyannis, A.; Consroe, P.; Roeske, W. R.; Yamamura, H.I. Life Sc. 1997, 61, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB1 receptor antagonists (e.g., LY-320135) (Felder, C. C.; Joyce, K. E.; Briley, E. J.; Glass, M.; Mackie, K. P.; Fahey, K. J.; Cullinan, G. J.; Hunden, D. C.; Johnson, D. W.; Chaney, M. O.; Koppel, G. A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284, 291). Recently, 3-alkyl-5,5xe2x80x2-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts, S. J.; Hermans, E.; Poupaert, J. H., Lambert, D. M. Biorg. Med.Chem. Lett. 1999, 9, 2233). Interestingly, many CB1 receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R. S.; Burkey, T. H.; Consroe, P.; Roeske, W. R.; Yamamura, H. I. Eur. J. Pharmacol. 1997, 334, R1). Recent reviews provide a nice overview of the current status in the cannabinoid research area (Mechoulam, R.; Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199. Lambert, D. M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998, 359, 1).
It has now surprisingly been found that the novel 4,5-dihydro-1H-pyrazole compounds of the formula (I), prodrugs thereof, tautomers thereof, stereoisomers thereof, and salts thereof 
wherein
R represents phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different and are chosen from
C1-3-alkyl, C1-3-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, monoalkyl (C1-2)-amino, dialkyl (C1-2)-amino, monoalkyl (C1-2)-amido, dialkyl (C1-2)-amido, (C1-3)-alkyl sulfonyl, dimethylsulfamido, C1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
xe2x80x83or R represents naphthyl,
R1 represents phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different and are chosen from
C1-3-alkyl, C1-3-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, monoalkyl (C1-2)-amino, dialkyl (C1-2)-amino, monoalkyl (C1-2)-amido, dialkyl (C1-2)-amido, (C1-3)-alkyl sulfonyl, dimethylsulfamido, C1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl,
xe2x80x83or R1 represents naphthyl,
R2 represents hydrogen, hydroxy, C1-3-alkoxy, acetyloxy or propionyloxy,
Aa represents one of the groups (i), (ii), (iii), (iv) or (v) 
wherein
R4 represents hydrogen, C1-8 branched or unbranched alkyl or C3-8 cycloalkyl; and when R5 represents hydrogen, R4 optionally further represents acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl or pyridyl,
R5 represents hydrogen, C1-8 branched or unbranched alkyl or C3-8 cycloalkyl,
R6 represents hydrogen or C1-3 unbranched alkyl,
Bb represents sulfonyl or carbonyl,
R3 represents benzyl, phenyl, thienyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents Y, which are the same or different, or R3 represents C1-8 branched or unbranched alkyl or C3-8 cycloalkyl, or R3 represents naphthyl,
can be potent and/or selective antagonists of the cannabis CB1-receptor.
Due to the potent CB1 antagonistic activity possible, the compounds according to the invention can be suitable for use in the treatment of one or more psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson""s disease, Alzheimer""s disease, epilepsy, Huntington""s disease, Tourette""s syndrome, cerebral ischaemia, and/or for the treatment of pain disorders and/or other CNS-diseases such as those involving cannabinoid neurotransmission, and/or in the treatment of gastrointestinal disorders and/or cardiovascular disorders. Thus, the invention further relates to methods for treating a human or animal patient in need of such treating for one or more of these disorders. A method of treating according to the invention comprises administering a compound of formula (I) in an amount efficacious for the treating.
The affinity of representative compounds of the invention for cannabinoid CB1 receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CB1 receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
The cannabinoid CB1 antagonistic activity of representative compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB1 receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB1 receptors by CB1 receptor agonists (e.g., CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB1 receptor-mediated response can be antagonised by CB1 receptor antagonists such as by many of the compounds of the invention.
At least one center of chirality is present (at the C4 position of the 4,5-dihydro-1H-pyrazole moiety) in the compounds of the formula (I). The invention relates both to racemates, mixtures of diastereomers, and the individual stereoisomers of the compounds having formula (I). The invention further relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
Thus, xe2x80x9ccompound of formula (I)xe2x80x9d and xe2x80x9ccompound having formula (I)xe2x80x9d refer to any compound of formula (I), any prodrug thereof, any tautomer thereof, any stereoisomer thereof, and any salt thereof, unless indicated otherwise. One of ordinary skill in the art will recognize that E- and Z-isomers are a subset of, and are included within, xe2x80x9cstereoisomers.xe2x80x9d
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid carrier materials. Thus, the invention also relates to compositions comprising at least one compound of formula (I) and at least one auxiliary substance. The invention also relates to methods for preparing a composition comprising mixing at least one compound of the formula (I) with at least one auxiliary substance. Many suitable auxiliary substances are readily known to those of ordinary skill in the art; care should be taken so that the selection of the at least one auxiliary substance will not, or will not substantially, adversely affect the desired properties of the composition.
If a composition according to the invention is intended for use in treating one or more of the disorders described above, then the composition may comprise at least one compound of formula (I) in an amount effective for the respective treating.
The invention also relates to processes for preparing a compound of formula (I).
The compounds of the invention having formula (III (vide infra), wherein R2 represents hydrogen, can be obtained according to methods known, for example, those disclosed in EP 0021506 and DE 2529689, the disclosures of which are incorporated herein by reference.
A suitable synthesis for the compounds according to the present invention is the following:
Synthesis route A (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above).
In each of the following formulae, the radicals are as defined in formula (I), unless otherwise indicated.
Step 1 of route A
Reaction of a compound having formula (II) 
with hydrazine or hydrazine hydrate. This reaction gives a compound having formula (III) 
wherein R2 represents a hydroxy group. This reaction, in some embodiments, is carried out in a polar solvent, such as, for example, ethanol. The invention also relates to novel compounds which can be intermediates in the preparation of compounds of formula (I). For example, compounds having formula (III) wherein R2 represents a hydroxy group and wherein R and R1 have the meaning as described herein above for compounds of formula (I) are new.
Step 2 of route A
Reaction of a compound having formula (III) with a compound having formula (IVa) or a compound having formula (IVb) 
wherein R7 represents a lower alkyl group, such as, for example, 2-methyl-2-thiopseudourea, or with a suitable salt form thereof in the presence of a base. In the present application, xe2x80x9clower alkyl groupxe2x80x9d means a straight, branched, or cyclic alkyl moiety having, for example, one to eight carbon atoms, which is unsubstituted or substituted by one or more radicals which do not substantially adversely affect the progress of the reaction. This reaction gives a 4,5-dihydro-1H-pyrazole-1-carboxamidine compound having formula (V) 
wherein Aa has the meaning (i) or (ii) as described herein above. Compounds having formula (V) wherein Aa has the meaning (i) or (ii) as described herein above and wherein R, R1 and R2 have the meaning as described herein above for compounds of the formula (I) are new.
Alternatively, a compound having formula (III) is reacted with a so-called guanylating agent. Examples of such guanylating agents are 1H-pyrazole-1-carboxamidine and its salts (for example the hydrochloride salt) and 3,5-dimethyl-1H-pyrazole-1-carboxamidine and its salts (for example the nitrate salt) and the like. This reaction gives a carboxamidine compound having formula (V).
Alternatively, a compound having formula (III) is reacted with a so-called protected guanylating agent. Examples of such protected guanylating agents are N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine, N-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and N,Nxe2x80x2-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and the like. This reaction gives, after deprotection, a compound having formula (V).
Step 3 of route A
The compound having formula (V) is reacted with an optionally substituted compound of the formula R3-SO2X or R3-COX, wherein R3 has the above mentioned meaning and X represents a halogen atom. This reaction, in some embodiments, is carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile. This reaction gives a compounds of formula (I) wherein Bb represents a sulfonyl group or a carbonyl group, respectively.
Synthesis route A1 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above)
Step 1 of route A1
Reaction of a compound having formula (III) 
with a thioisocyanate compound having formula (VI). 
This reaction, in some embodiments, is carried out in an inert organic solvent, such as for example acetonitrile. This reaction gives a thiocarboxamide compound having formula (VIl). Compounds having formula (VII) wherein R, R1, R2, R3 and Bb have the meanings as described herein above for compounds of formula (I) are new. 
Step 2 of route A1
Reaction of a compound having formula (VII) with an amine in the presence of a mercury(II) salt, such as for example HgCl2, gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above. xe2x80x9cAminexe2x80x9d refers to a nitrogen-containing species appropriately substituted with, for example R4 and R5 as defined above for the formula (I). The amine can be, for example, methylamine. This reaction, in some embodiments, is carried out in a polar organic solvent, such as, for example, acetonitrile.
Synthesis route A2 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above)
Step 1 of route A2
Reaction of a compound having formula III 
with a carbamate ester compound having formula (VIII). 
wherein R7 represents a lower alkyl group, for example methyl. This reaction, in some embodiments, is carried out in an inert organic solvent, such as for example 1,4-dioxane. This reaction gives a 4,5-dihydropyrazole-1-carboxamide compound having formula (IX). Compounds having formula (IX) wherein R, R1, R2, R3 and Bb have the meaning as described herein above for compounds of formula (I) are new. 
Step 2 of route A2
Reaction of a compound having formula (IX) with a halogenating agent, such as for example PCl5, gives a 4,5-dihydropyrazole-1-carboximidoyl halogenide compound having formula (X) 
wherein R8 represents a halogen atom, such as for example chloro. This reaction, in some embodiments, is carried out in an inert organic solvent, such as for example chlorobenzene.
Compounds having formula (X) wherein R, R1, R2, R3 and Bb have the meaning as described herein above for compound (I) and wherein R8 represents a halogen atom are new.
Step 3 of route A2
Reaction of a compound having formula (X) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
This reaction, in some embodiments, is carried out in an inert organic solvent, such as for example dichloromethane.
Synthesis route A3 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above)
Step 1 of route A3
Reaction of a compound having formula III 
with a dithioimidocarbonic ester compound having formula (XI). 
wherein R9 represents a C1-3 alkyl group. This reaction, in some embodiments, is carried out in a polar organic solvent, such as for example acetonitrile. This reaction gives a carboximidothioic ester compound having formula (XII) 
wherein R9 represents a C1-3 alkyl group. Compounds having formula (XII) wherein R, R1, R2, R3 and Bb have the meaning as described herein above for compounds of formula (I) and wherein R9 represents a C1-3 alkyl group are new.
Step 2 of route A3
Reaction of a compound having formula (XII) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
This reaction, in some embodiments, is carried out in a polar organic solvent, such as, for example, methanol.
Synthesis route B (for compounds having formula (I), wherein Aa has the meaning (iii) or (iv) as described herein above)
Step 1 of route B
Reaction of a compound having formula (III) 
with a compound having formula (XIII), or a compound having formula (XIV), respectively 
wherein Bb, R3 and R6 have the above mentioned meanings and Z represents a so-called leaving group. One of ordinary skill in the art will recognize suitable leaving groups, such as, for example, alkoxy radicals, halides, tosylates, triflates, and any moiety which tends to facilitate the reaction in the manner of a leaving group.
These reactions give compounds having formula (I), wherein Aa has the meaning (iii) or (iv), respectively.
Synthesis route C (for compounds having formula (I), wherein Aa has the meaning (v) as described herein above)
Step 1 of route C
Reaction of a compound having formula (III) 
with an aziridine compound having formula (XV), or a compound having formula (XVI), respectively 
wherein R6 has the above mentioned meaning, Z represents a so-called leaving group and Prot represents a so-called protective group, such as tert-butoxycarbonyl, benzyloxycarbonyl and the like.
These reactions give compounds having formula (XVII) 
wherein Aa has the meaning (v) as described herein above. Compounds having formula (XVII) wherein R, R1 and R2 have the meaning as described herein above for compounds of formula (I) and wherein Aa has the meaning (v) as described herein above and wherein Prot represents a so-called protective group are new.
Subsequent removal of the so-called protective group according to known methods (see for example: T. W. Greene, P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, third edition, John Wiley and Sons, Inc., New York, 1999) gives compounds of formula (V), wherein Aa has the meaning (v) as described herein above). Compounds having formula (V) wherein R, R1 and R2 have the meaning as described herein above for compounds of formula (I) and wherein Aa has the meaning (v) as described herein above are new.
Step 2 of route C
The compound having formula (V), wherein Aa has the meaning (v) as described herein above, is reacted with an optionally substituted compound of the formula R3xe2x80x94SO2X or R3xe2x80x94COX, wherein R3 has the above mentioned meaning and X is halogen. This reaction, in some embodiments, is carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile. This reaction gives compounds of formula (I) wherein Bb represents a sulfonyl group or carbonyl group respectively.
Alternatively, the above mentioned compound having formula (V) can be reacted with a compound of the formula R3xe2x80x94COOH via formation of an active ester or in the presence of a so-called coupling reagent.
The preparation of representative compounds in accordance with the invention is illustrated in the following examples.